PROJECT SUMMARY Memory impairment is a defining characteristic of many neuropsychiatric disorders, however our understanding of the neurobiological mechanisms of memory dysfunction and ability to therapeutically address these symptoms remain inadequate. The sex steroid hormone 17?-estradiol (E2) is a powerful regulator of learning and memory and has profound effects in the hippocampus, a region critical to memory formation. E2-induced signaling within the hippocampus is necessary for memory consolidation, but the molecular mechanisms producing this effect are still not fully defined. Therefore, the long-term goal of our research is to determine the molecular mechanisms through which E2 regulates hippocampal memory formation. The overall objective of this application is to determine the extent to which the ECM molecules MMP-9 and ?1-integrin are necessary for E2 to enhance hippocampal memory in both male and female mice. Based on previous data showing that MMP-9 and ?1-integrin work together as critical regulators of hippocampal plasticity, our central hypothesis is that E2 enhances hippocampal memory consolidation through modification of the ECM via increased MMP-9 enzymatic activity and subsequent activation of cell-surface ?1-integrin receptors. The rationale for this work is that by uncovering novel mechanisms of E2 action in regulating hippocampal plasticity and memory, we will improve our understanding, and ability to therapeutically target, estrogenic regulation of hippocampal dysfunction. Our central hypothesis will be tested in two specific aims: 1) determine the extent to which estrogenic regulation of MMP-9 contributes to hippocampal memory enhancement, and 2) determine the extent to which estradiol and ?1-integrin receptors interact to produce hippocampal memory enhancement. Both aims will use a combination of biochemical and behavioral methods to characterize the mechanisms and outcomes of E2 regulation of the hippocampal ECM. First, E2 will be directly infused into the dorsal hippocampus of male and female mice and the effects on MMP-9 or ?1-integrin expression and activity will be assessed. Then, using one-trial learning tasks and intracranial infusion of pharmacological inhibitors, we will determine the extent to which MMP-9 and ?1-integrin influence estrogenic regulation of memory consolidation. This work is innovative in that it represents a fundamental shift from the conventional focus on intracellular signaling mechanisms to consider the potentially important contribution of the ECM in estrogenic regulation of memory consolidation. By directly assessing the contributions of the ECM to estrogenic memory regulation, we will advance the existing model of E2 signaling in the hippocampus to integrate extracellular and intracellular signaling processes. This contribution is significant because it will provide essential foundational knowledge about the mechanisms through which estradiol regulates memory formation in the male and female brain, which will serve to generate new putative therapeutic targets for memory dysfunction.